Emerging strategies for tissue engineering in vascularized composite allotransplantation: A review.

Vascularized composite allotransplantation (VCA), which can effectively improve quality of life, is a promising therapy for repair and reconstruction after face or body trauma. However, intractable issues are associated with VCA, such as the inevitable multiple immunogenicities of different tissues that cause severe rejection, the limited protocols available for clinical application, and the shortage of donor sources. The existing regimens used to extend the survival of patients receiving VCAs and suppress rejection are generally the lifelong application of immunosuppressive drugs, which have side effects. Consequently, studies aiming at tissue engineering methods for VCA have become a topic. In this review, we summarize the emerging therapeutic strategies for tissue engineering aimed to prolong the survival time of VCA grafts, delay the rejection and promote prevascularization and tissue regeneration to provide new ideas for future research on VCA treatment.

A Review on Pig-to-Human Organ Transplantation / 中国生物化学与分子生物学报

Xenotransplantation holds the promise of being used to address the imbalance between organ supply and demand for clinical transplantation. Pigs have natural features that make them more suitable donors for transplant organs than non-human primates. A series of biological barriers that arise after pig organ transplantation have been overcome by genetic engineering and pharmacological suppression. Mean- while, the gradual maturity of the genetic engineering technology has been significantly optimized for suit- able pigs for xenotransplantation, and promoted the development of pig organ transplantation research. Although it will take time for pig organ xenotransplantation to enter the clinical trial stage, recent studies conducted in a few brain-dead or critically ill patients have exhibited the great potential of porcine xeno- transplantation in solving the imbalance between supply and demand of organs for clinical transplantation.

Advances in Innate Immunity to Overcome Immune Rejection during Xenotransplantation.

Transplantation is an effective approach for treating end-stage organ failure. There has been a long-standing interest in xenotransplantation as a means of increasing the number of available organs. In the past decade, there has been tremendous progress in xenotransplantation accelerated by the development of rapid gene-editing tools and immunosuppressive therapy. Recently, the heart and kidney from pigs were transplanted into the recipients, which suggests that xenotransplantation has entered a new era. The genetic discrepancy and molecular incompatibility between pigs and primates results in barriers to xenotransplantation. An increasing body of evidence suggests that innate immune responses play an important role in all aspects of the xenogeneic rejection. Simultaneously, the role of important cellular components like macrophages, natural killer (NK) cells, and neutrophils, suggests that the innate immune response in the xenogeneic rejection should not be underestimated. Here, we summarize the current knowledge about the innate immune system in xenotransplantation and highlight the key issues for future investigations. A better understanding of the innate immune responses in xenotransplantation may help to control the xenograft rejection and design optimal combination therapies.

Genetic engineering of pigs for xenotransplantation to overcome immune rejection and physiological incompatibilities: The first clinical steps.

Xenotransplantation has the potential to solve the shortfall of human organ donors. Genetically modified pigs have been considered as potential animal donors for human xenotransplantation and have been widely used in preclinical research. The genetic modifications aim to prevent the major species-specific barriers, which include humoral and cellular immune responses, and physiological incompatibilities such as complement and coagulation dysfunctions. Genetically modified pigs can be created by deleting several pig genes related to the synthesis of various pig specific antigens or by inserting human complement- and coagulation-regulatory transgenes. Finally, in order to reduce the risk of infection, genes related to porcine endogenous retroviruses can be knocked down. In this review, we focus on genetically modified pigs and comprehensively summarize the immunological mechanism of xenograft rejection and recent progress in preclinical and clinical studies. Overall, both genetically engineered pig-based xenografts and technological breakthroughs in the biomedical field provide a promising foundation for pig-to-human xenotransplantation in the future.

A Fresh Glimpse into Cartilage Immune Privilege.

The increasing prevalence of degenerative cartilage disorders in young patients is a growing public concern worldwide. Cartilage's poor innate regenerative capacity has inspired the exploration and development of cartilage replacement treatments such as tissue-engineered cartilages and osteochondral implants as potential solutions to cartilage loss. The clinical application of tissue-engineered implants is hindered by the lack of long-term follow-up demonstrating efficacy, biocompatibility, and bio-integration. The historically reported immunological privilege of cartilage tissue was based on histomorphological observations pointing out the lack of vascularity and the presence of a tight extracellular matrix. However, clinical studies in humans and animals do not unequivocally support the immune-privilege theory. More in-depth studies on cartilage immunology are needed to make clinical advances such as tissue engineering more applicable. This review analyzes the literature that supports and opposes the concept that cartilage is an immune-privileged tissue and provides insight into mechanisms conferring various degrees of immune privilege to other, more in-depth studied tissues such as testis, eyes, brain, and cancer.

Clinical Evaluation of Autologous and Allogeneic Stem Cell Therapy for Intrauterine Adhesions: A Systematic Review and Meta-Analysis.

Objective: Intrauterine adhesions (IUAs) are a major cause of female infertility. Stem cells can be used to restore endometrial function owing to their regenerative abilities. We compared the safety and efficacy of autologous and allogeneic stem cell treatments in patients with recurrent IUA after conventional therapy based on a systematic review of the related literature. Methods: The PubMed, Embase, and Cochrane databases were systematically searched. All analysis were performed using Review Manager 5.4. We compared improvements in endometrial thickness, pregnancy rates, menstruation, and side effects after autologous and allogeneic stem cell therapy. The study was registered with PROSPERO, CRD 42022322870. Results: Our search returned 154 reports, 10 of which met the inclusion criteria, representing 116 patients. Of these, 44 patients in two studies were treated with allogeneic stem cells and 72 patients in eight studies were treated with autologous stem cells. Improvements in endometrial thickness and pregnancy rates after intrauterine device treatment were compared between the autologous and allogeneic stem cell groups. Endometrial thickness increased more after autologous stem cell IUA treatment (mean difference, 1.68; 95% confidence interval [CI]: 1.30-2.07; P < 0.00001), and the pregnancy rate was also improved (relative risk, 1.55; 95% CI: 1.19-2.02, P < 0. 001). No obvious and serious adverse reactions were observed during stem cell therapy in either group. Conclusions: This meta-analysis and systematic review of the results of randomized trials of autologous and allogeneic stem cell treatments for IUA suggests that autologous stem cells have a better effect in improving the endometrium thickness and pregnancy rate. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022322870.

Corneal Transplant Follow-up Study II: a randomised trial to determine whether HLA class II matching reduces the risk of allograft rejection in penetrating keratoplasty.

PURPOSE: A randomised trial to test the hypothesis that human leucocyte antigen (HLA) class II matching reduces the risk of allograft rejection in high-risk penetrating keratoplasty (PK). METHODS: All transplants were matched for HLA class I antigens (≤2 mismatches at the A and B loci) and corneas were allocated to patients by cohort minimisation to achieve 0, 1 or 2 HLA class II antigen mismatches. The corneal transplants (n=1133) were followed for 5 years. The primary outcome measure was time to first rejection episode. RESULTS: Cox regression analysis found no influence of HLA class II mismatching on risk of immunological rejection (HR 1.13; 95% CI 0.79 to 1.63; p=0.51). The risk of rejection in recipients older than 60 years was halved compared with recipients ≤40 years (HR 0.51; 95% CI 0.36 to 0.73; p=0.0003). Rejection was also more likely where cataract surgery had been performed after PK (HR 3.68; 95% CI 1.95 to 6.93; p<0.0001). In univariate analyses, preoperative factors including chronic glaucoma (p=0.02), vascularisation (p=0.01), inflammation (p=0.03), ocular surface disease (p=0.0007) and regrafts (p<0.001) all increased the risk of rejection. In the Cox model, however, none of these factors was individually significant but rejection was more likely where≥2 preoperative risk factors were present (HR 2.11; 95% CI 1.26 to 3.47; p<0.003). CONCLUSIONS: HLA class II matching, against a background of HLA class I matching, did not reduce the risk of allograft rejection. Younger recipient age, the presence of ≥2 preoperative risk factors and cataract surgery after PK all markedly increased the risk of allograft rejection. TRIAL REGISTRATION NUMBER: ISRCTN25094892.

Engineered Small Extracellular Vesicles as a FGL1/PD-L1 Dual-Targeting Delivery System for Alleviating Immune Rejection.

There is an urgent need for developing new immunosuppressive agents due to the toxicity of long-term use of broad immunosuppressive agents after organ transplantation. Comprehensive sample analysis revealed dysregulation of FGL1/LAG-3 and PD-L1/PD-1 immune checkpoints in allogeneic heart transplantation mice and clinical kidney transplant patients. In order to enhance these two immunosuppressive signal axes, a bioengineering strategy is developed to simultaneously display FGL1/PD-L1 (FP) on the surface of small extracellular vesicles (sEVs). Among various cell sources, FP sEVs derived from mesenchymal stem cells (MSCs) not only enriches FGL1/PD-L1 expression but also maintain the immunomodulatory properties of unmodified MSC sEVs. Next, it is confirmed that FGL1 and PD-L1 on sEVs are specifically bound to their receptors, LAG-3 and PD-1 on target cells. Importantly, FP sEVs significantly inhibite T cell activation and proliferation in vitro and a heart allograft model. Furthermore, FP sEVs encapsulated with low-dose FK506 (FP sEVs@FK506) exert stronger effects on inhibiting T cell proliferation, reducing CD8+ T cell density and cytokine production in the spleens and heart grafts, inducing regulatory T cells in lymph nodes, and extending graft survival. Taken together, dual-targeting sEVs have the potential to boost the immune inhibitory signalings in synergy and slow down transplant rejection.

The role of soluble programmed death protein-1 (sPD-1) and soluble programmed death ligand-1 (sPD-L1) in rat corneal transplantation rejection.

BACKGROUND: Immunological rejection is one of the problems in corneal transplantation. Recently, some research found out that soluble programmed death protein-1 (sPD-1) and soluble programmed death ligand protein-1 (sPD-L1) play a significant role in immunologic suppression. OBJECTIVES: To explore expression of sPD-1 and sPD-L1 in a penetrative corneal transplantation model and its relationship with transplant rejection. MATERIAL AND METHODS: Autologous corneal transplantation rat models and allogeneic corneal transplantation rat models were used as the control group and the experimental group, respectively. Changes of the transplanted grafts were observed under a slit-lamp microscope. Hematoxylin-eosin (H&E) staining was applied to examine the histopathological features of the corneal grafts. Flow cytometry was used to analyze CD4+CD25+Treg in the serum and spleen. The sPD-1, sPD-L1, interleukin 10 (IL-10) and interleukin 4 (IL-4) levels in serum and the aqueous humor of the rats were detected using enzyme-linked immunosorbent assay (ELISA). RESULTS: After the operation, no transplant rejection occurred in the control group. Flow cytometry results showed that expressions of CD4+CD25+Treg in serum in the experimental group were lower than those in the control group (p < 0.05). The ELISA results showed that after the operation, sPD-1 and sPD-L1 expression levels in serum in the experimental group were higher than in the control group (all p < 0.05). After the operation, lL-10 and IL-4 content in serum in the experimental group was lower than in the control group (all p < 0.05). The sPD-1/sPD-L1 ratio in the experimental group was higher than in the control group. CONCLUSIONS: Increases of sPD-1 content and decreases of CD4+CD25+Treg, IL-10 and IL-4 levels may be involved in corneal allograft rejection. Dynamic detection of the content of sPD-1 and sPD-L1 in serum and aqueous humor after the operation would help in understanding the local immune response in a clinical setting and predicting the occurrence of corneal graft rejection.

Clinical and immunopathological study of rejection after bioengineered keratoplasty: a report of 5 cases / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM: To explore the mechanism of rejection of bioengineered keratoplasty by the laser confocal microscope and immunopathological studies.<p>METHODS: Retrospective case study. Five patients(5 eyes)who underwent bioengineered keratoplasty for infectious keratitis from Sep.2018 to Dec.2020 and were immunologically rejected included. All observers were monocular. Slit-lamp was used to examine corneal transparency and corneal neovascularization. The cornea was dynamically observed under laser confocal microscopy, the density of subepithelial langerhans cells and stromal inflammatory cells was recorded after graft rejection, and the contralateral eye was used as the control group for statistical analysis. The infiltration and distribution of CD4⁺ cells, CD8⁺ cells and inflammatory cells were observed after immunohistochemical staining of bioengineered corneas during corneal allograft.<p>RESULTS: Confocal laser microscopy showed that a large number of langerhans cells were activated under the corneal epithelium of the intraoperative eye, and the activation ratio was significantly different from that of the contralateral eye(χ²=38.29, <i>P</i><0.001). The stromal layer was rich in inflammatory cells, which was significantly different from that of the contralateral eye(<i>t</i>=32.5, <i>P</i><0.05). Immunohistochemical staining and HE staining were performed on the bioengineering corneal tissue. CD4⁺ and CD8⁺ cells were observed in all corneal stromal layers, and only one case had a large number of eosinophils.<p>CONCLUSION: Immunopathology of rejection after bioengineered keratoplasty confirmed that T-cell-mediated cellular immunity plays an important role in the pathogenesis, and hypersensitivity to xenoantigen may be involved in it.

Immunomodulatory effect of human adipose derived mesenchymal stem cells on skin transplantation between different mouse strains / 中国组织工程研究

BACKGROUND: Skin transplantation is one of the most effective methods for treating large-area burns. How to effectively suppress the immune rejection after allogeneic skin transplantation is a problem that needs to be solved urgently. OBJECTIVE: To investigate the effect of human adipose derived mesenchymal stem cells (hADSCs) on the immunoregulation of skin grafts in different strains of mice. METHODS: Isolated hADSCs were cultured to the 3rd generation. Sixty ICR neonatal mice, 2-4 days of age, were randomly divided into four groups (n=15). The skin tissues of ICR neonatal mice were transplanted into adult C57BL/6 mice to establish a different strain of mouse skin graft immune rejection model. PBS and low dose (5×104), medium dose (10×104), high dose (20×104) hADSCs were injected into the model mice through tail vein, and the survival time of transplanted skin in each group was recorded. On the 7th day after operation, five mice from each group were randomly selected to remove their spleen and serum, and the expression of immune factors interleukin-10, tumor necrosis factor-α and interferon-γ were detected by RT-PCR and ELISA respectively. The transplanted part of the skin was taken to make pathological sections for observing the infiltration of lymphocytes. RESULTS AND CONCLUSION: Compared with the PBS group, the survival time of the skin was prolonged in the low dose hADSCs group; however, there was no significant difference between the two groups (P > 0.05). Compared with the PBS and low dose hADSCs groups, the survival time of the skin was significantly increased in the medium and high dose groups (P 0.05). Compared with the PBS group, the relative expression of tumor necrosis factor-α and interferon-γ in the spleen and serum was significantly decreased in the low, medium and high dose hADSCs groups (P < 0.05), whereas the level of interleukin-10 was significantly elevated in the medium and high dose hADSCs groups (P < 0.05). To conclude, the appropriate dose of hADSCs can significantly prolong the survival time of transplanted skin between different strains of mice, by regulating the expression of related immune factors in the recipient mice.

Immune reaction and regulation in transplantation based on pluripotent stem cell technology.

The development of pluripotent stem cell (PSC)-based technologies provides us a new therapeutic approach that generates grafts for transplantation. In order to minimize the risk of immune reaction, the banking of induced pluripotent stem cells (iPSCs) from donors with homozygous human leukocyte antigen (HLA) haplotype is planned in Japan. Even though pre-stocked and safety validated HLA-homozygous iPSCs are selected, immunological rejection may potentially occur because the causes of rejection are not always due to HLA mismatches. A couple of studies concerning such immunological issues have reported that genetic ablation of HLA molecules from PSC combined with gene transduction of several immunoregulatory molecules may be effective in avoiding immunological rejection. Also, our research group has recently proposed a concept that attempts to regulate recipient immune system by PSC-derived immunoregulatory cells, which results in prolonged survival of the same PSC-derived allografts. PSC-based technologies enable us to choose a new therapeutic option; however, considering its safety from an immunological point of view should be of great importance for safe clinical translation of this technology.

Machine Perfusion of Extended Criteria Donor Organs: Immunological Aspects.

Due to higher vulnerability and immunogenicity of extended criteria donor (ECD) organs used for organ transplantation (Tx), the discovery of new treatment strategies, involving tissue allorecognition pathways, is important. The implementation of machine perfusion (MP) led to improved estimation of the organ quality and introduced the possibility to achieve graft reconditioning prior to Tx. A significant number of experimental and clinical trials demonstrated increasing support for MP as a promising method of ECD organ preservation compared to classical static cold storage. MP reduced ischemia-reperfusion injury resulting in the protection from inadequate activation of innate immunity. However, there are no general agreements on MP protocols, and clinical application is limited. The objective of this comprehensive review is to summarize literature on immunological effects of MP of ECD organs based on experimental studies and clinical trials.

Busulfan Combined with Immunosuppression Allows Efficient Engraftment of Gene-Modified Cells in a Rhesus Macaque Model.

Busulfan conditioning is utilized for hematopoietic stem cell (HSC) depletion in the context of HSC gene-therapy conditioning but may result in insufficient immunosuppression. In this study, we evaluated whether additional immunosuppression is required for efficient engraftment of gene-modified cells using a rhesus HSC lentiviral gene-therapy model. We transduced half of rhesus CD34+ cells with an enhanced green fluorescent protein (GFP)-encoding vector (immunogenic) and the other half with a γ-globin-encoding vector (no predicted immunogenicity). After autologous transplantation of both transduced cell populations following myeloablative busulfan conditioning (5.5 mg/kg/day for 4 days), we observed immunological rejection of GFP-transduced cells up to 3 months post-transplant and stable engraftment of γ-globin-transduced cells in two animals, demonstrating that ablative busulfan conditioning is sufficient for engraftment of gene-modified cells producing non-immunogenic proteins but insufficient to permit engraftment of immunogenic proteins. We then added immunosuppression with abatacept and sirolimus to busulfan conditioning and observed engraftment of both GFP- and γ-globin-transduced cells in two animals, demonstrating that additional immunosuppression allows for engraftment of gene-modified cells expressing immunogenic proteins. In conclusion, myeloablative busulfan conditioning should permit engraftment of gene-modified cells producing non-immunogenic proteins, while additional immunosuppression is required to prevent immunological rejection of a neoantigen.

Understanding the Immunological Mechanisms of Mesenchymal Stem Cells in Allogeneic Transplantation: From the Aspect of Major Histocompatibility Complex Class I.

Mesenchymal stem cell (MSC) transplantation therapy appears to be an ideal strategy for repairing structural defects and restoring the functions of diseased tissues and organs. Additionally, MSCs are also used as immunosuppressants in allogeneic organ transplantation. However, owing to their inherent immunogenicity, MSC transplantation can induce the activation of an immune response, which can lead to the death and clearance of the transplanted MSCs. Major histocompatibility complex (MHC) molecules are responsible for antigen presentation, help T lymphocytes to recognize endogenous/extrinsic antigens, and trigger immune activation. Many studies have shown that MHC molecules (particularly class I) play key roles in the immunogenicity of MSCs. This review, therefore, focuses on the relationship between MHC-I surface expression on MSCs and its immunogenicity, as well as potential strategies to overcome the hurdle of MHC incompatibility.

Xenotransplantation: Current Status in Preclinical Research.

The increasing life expectancy of humans has led to a growing numbers of patients with chronic diseases and end-stage organ failure. Transplantation is an effective approach for the treatment of end-stage organ failure; however, the imbalance between organ supply and the demand for human organs is a bottleneck for clinical transplantation. Therefore, xenotransplantation might be a promising alternative approach to bridge the gap between the supply and demand of organs, tissues, and cells; however, immunological barriers are limiting factors in clinical xenotransplantation. Thanks to advances in gene-editing tools and immunosuppressive therapy as well as the prolonged xenograft survival time in pig-to-non-human primate models, clinical xenotransplantation has become more viable. In this review, we focus on the evolution and current status of xenotransplantation research, including our current understanding of the immunological mechanisms involved in xenograft rejection, genetically modified pigs used for xenotransplantation, and progress that has been made in developing pig-to-pig-to-non-human primate models. Three main types of rejection can occur after xenotransplantation, which we discuss in detail: (1) hyperacute xenograft rejection, (2) acute humoral xenograft rejection, and (3) acute cellular rejection. Furthermore, in studies on immunological rejection, genetically modified pigs have been generated to bridge cross-species molecular incompatibilities; in the last decade, most advances made in the field of xenotransplantation have resulted from the production of genetically engineered pigs; accordingly, we summarize the genetically modified pigs that are currently available for xenotransplantation. Next, we summarize the longest survival time of solid organs in preclinical models in recent years, including heart, liver, kidney, and lung xenotransplantation. Overall, we conclude that recent achievements and the accumulation of experience in xenotransplantation mean that the first-in-human clinical trial could be possible in the near future. Furthermore, we hope that xenotransplantation and various approaches will be able to collectively solve the problem of human organ shortage.

Research progress in uterus allotransplantation / 中国免疫学杂志

The application of microsurgery and immunosuppressive agents have led to remarkable progress in uterus allotransplantation for patients with absolute uterine infertility. At present, more than 40 cases of human uterus transplantation have been successfully carried out worldwide, and 12 healthy newborn babies have been delivered using cesarean section. However, selection of transplant donors and recipient, in vitro uterine perfusion, the immunosuppressive therapy and characteristics of graft rejection after uterus allotransplantation are worthy of attention. This article reviews the research progress in uterus allotransplantation.

Relationship between cellular rejection and development of rat transplanted metanephroi from different gestational ages / 中华器官移植杂志

Objective To explore the relationship between cellular rejection and the development of allo-or xenografted primordia from different gestational ages .Methods Whole rat metanephroi from embryonic day E14～ E19 were transplanted into omenta of outbred (SD → SD ,6 groups ,n≥10 each ;E15-E17SDCsA ,3 groups ,n=15 each) ,syngeneic (Lewis→Lewis ,5 groups ,n=8 each) ,allogeneic (Lewis→BN ,E15BN n= 6 each E15BNCsA n= 10 each ,E16BNCsA n= 10 each) rats and xenogeneic (Lewis→C57groups ,E15C57 n=10 each ,E15C57CsA ,n=8 each ;Lewis→Balb/c nude mice ,3 groups ,n=10 each) recipients .Histopathology ,Banff's grading and electron microscopy (EM ) were utilized for assessing the graft development .Similarly ,biochemical indicators and creatinine clearances were measured .Results At 4 weeks post-transplantation , in SD → SD groups ,E14-E17SD metanephroi developed with Banff ' s rejections . E14/E15SD was significantly lighter than E16/E17SD ( P< 0 .01 );E18/E19SD barely developed . After cyclosporine A (CsA , 8 mg·kg -1·d-1 )dosing ,Banff's rejection of E15-E17SDCsA group lessened significantly .In Lewis→BN ,E15BN metanephroi were completely rejected .After dosing CsA (12 mg·kg -1·d-1 ) ,E15BNCsA and E16BNCsA Banff ' s rejections became alleviated . Upon a discontinuation of CsA , both metanephroi were rejected . In Lewis → Lewis , E15 ～ E17Lewis metanephroi developed well . No significant difference existed in Banff's classification (P>0 .05) .E14Lewis and E18Lewis rats had significantly poorly differentiated metanephroi than those in E16 Lewis group .In Lewis→C57BL/6 , E15 metanephroi were rejected at Day 14 post-transplantation (n= 10) and no improvement was evident after CsA dosing (15 mg·kg -1·d-1 ,n=8) .In Lewis→Balb/c nude mice ,all E15～E17Balb/c metanephroi developed well .Both light microscopy and EM examination showed normal nephrons and collecting ducts and wet weight ,creatinine or urea nitrogen of effusion showed no significant difference (P>0 .05) .E15Lewis and E16Lewis had significantly different values of wet weight and creatinine clearances from those of E15SDCsA and E16SDCsA .E15SDCsA had the greatest wet weight and the lowest creatinine clearance rate (P< 0 .01) .Conclusions After controlling rejection during allo-and xenotransplantations ,E15 ,E16 and E17 rat metanephros have similar development characteristics . And cellular immunogenic factors still remain the major barriers to their developments .

Effect of compound betamethasone on immunological rejection after xenogeneic corneal lamellar transplantation / 国际眼科杂志(Guoji Yanke Zazhi)

AIM:To observe the sustained-release effect of compound betamethasone by subconjunctival injection on immunological rejection after ostrich-rabbit lamellar keratoplasty.METHODS:Sixteen healthy New Zealand white rabbits with 6wk old received corneal lamellar keratoplasty,and the corneal graft was ostrich acellular corneal stroma.After surgery all subjects were divided into two groups,Group A (experimental group) were administrated with subconjunctival injection of compound betamethasone injection (once every 7d),and Group B (control group) were administrated with subconjunctival injection of dexamethasone sodium phosphate (once every 7d).At 1,2wk,1,2mo after the surgery,rabbit corneas were taken for paraffin sections,and were observed with H-E staining,in the meantime changes of CD4+ and CD8+ T lymphocytes were observed by immunofluorescence.RESULTS:Two months after surgery,in Group A corneal grafts remained transparenct,and showed little neovascularization;HE staining and indirect immunofluorescence showed that only a few neutrophil infiltration,no CD4+ and CD8+T lymphocytes.In Group B,the inflammatory reaction was observable at different time points,the corneal graft was turbid;and the tissue sections and indirect immunofluorescence staining showed that neutrophil infiltration was predominant,and CD4+,CD8+T lymphocytes were also seen.CONCLUSION:Compound betamethasone is able to inhibit the ostrich-rabbit corneal transplantation immune rejection,prolong the survival time of the grafts.The present study lay the foundation for further research and clinical application.

After 12 consecutive miscarriages, a patient received immunosuppressive treatment and delivered an intact baby.

Aim: An immune etiology for idiopathic recurrent miscarriage is an important issue because a fetus is allogenetically different from the mother. Type 1 T helper (Th1) and Type 2 (Th2) cells have important functions in immune responses and there is a general agreement that pregnancy is associated with Th2 cell dominance. The purpose of this case report is to establish the effectiveness of an immunosuppressive treatment for a patient who had 11 consecutive miscarriages despite several treatments, such as anticoagulation, that showed elevated Th1/Th2 cell ratios. Methods: This patient visited our clinic following 11 consecutive miscarriages between 2009 and 2014 that occurred between 5 and 8 weeks' gestation. The Th1/Th2 cell ratio was evaluated after the 12th conception and she received an immunosuppressive treatment (tacrolimus; 1 mg/d). Results: The Th1/Th2 cell ratio was elevated after the 12th conception, but the patient miscarried, with a normal karyotype of chorionic villi despite the immunosuppressive treatment. After the 13th conception, she began receiving treatment with 2 mg/d of tacrolimus at 4 weeks' gestation, which was continued until delivery. Conclusion: For recurrent miscarriage cases that show an elevated Th1/Th2 cell ratio after achieving pregnancy, immunosuppressive treatment with tacrolimus could be effective.